Glibenclamide and glipizide show large substantial inter-individual variation in clinical efficacy, which may be resulted from the genetic differences of metabolic enzymes and transporters in individuals. This study purposed to investigate the effect of OATP1B3 and CYP2C9 genetic polymorphisms on the transport and metabolism of glibenclamide and glipizide in human. An LC-MS method was used to determine the uptake of glibenclamide and glipizide in OATP1B3, OATP1B3 (344T > G) and OATP1B3 (699G > A)-HEK293T cells and their metabolism in CYP2C9*1, *2 and *3 recombinase system. Glibenclamide can be taken in OATP1B3 (wild-type), OATP1B3 (344T > G) and OATP1B3 (699G > A)-HEK293T cells with the V_max values of 44.91 ± 7.97, 46.08 ± 8.69, and 37.31 ± 5.04 pmol/min/mg, while glipizide was taken in with V_max of 16.50 ± 3.64, 16.87 ± 4.23, and 13.42 ± 2.79 pmol/min/mg, respectively. The internal clearance of glibenclamide and glipizide in OATP1B3 (699G > A) was less than that in wild-type. Glibenclamide can be metabolized in CYP2C9*1, *2 and *3 recombinase system with the V_max values of 1.58 ± 0.71, 0.69 ± 0.25, and 0.41 ± 0.13 nmol/min/mg protein, while glipizide was metabolized with V_max of 8.82 ± 2.78, 5.99 ± 1.95, and 2.87 ± 1.03 nmol/min/mg protein, respectively. The internal clearance of glibenclamide and glipizide in CYP2C9*2 and *3 was markedly reduced compared to that in CYP2C9*1. These results collectively demonstrate that OATP1B3 (699G > A) and CYP2C9*2 and *3 have a significant influence on the transport and metabolism of glibenclamide and glipizide.

中文翻译：

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OATP1B3（699G> A）和CYP2C9 * 2，* 3显着影响格列本脲和格列吡嗪的转运和代谢。

格列本脲和格列吡嗪在临床疗效上存在较大的个体间差异，这可能是由于个体中代谢酶和转运蛋白的遗传差异所致。本研究旨在探讨OATP1B3和CYP2C9基因多态性对格列本脲和格列吡嗪在人体内的运输和代谢的影响。使用LC-MS方法确定glibenclamide和格列吡嗪在OATP1B3，OATP1B3（344T> G）和OATP1B3（699G> A）-HEK293T细胞中的摄取及其在CYP2C9 * 1，* 2和* 3重组酶系统中的代谢。格列本脲可用于OATP1B3（野生型），OATP1B3（344T> G）和OATP1B3（699G> A）-HEK293T细胞中，V _max值为44.91±7.97、46.08±8.69和37.31±5.04 pmol / min /毫克分别为16.50±3.64、16.87±4.23和13.42±2.79 pmol / min / mg。OATP1B3（699G> A）中格列本脲和格列吡嗪的内部清除率低于野生型。格列本脲可在CYP2C9 * 1，* 2和* 3重组酶系统中代谢，V _max值为1.58±0.71、0.69±0.25和0.41±0.13 nmol / min / mg蛋白，而格列吡嗪则以V _max为8.82代谢蛋白质分别为±2.78、5.99±1.95和2.87±1.03 nmol / min / mg。与CYP2C9 * 1相比，CYP2C9 * 2和* 3中格列本脲和格列吡嗪的内部清除率明显降低。这些结果共同表明，OATP1B3（699G> A）和CYP2C9 * 2和* 3对格列本脲和格列吡嗪的转运和代谢有重要影响。